Drugs that target monoaminergic transmission represent a first line treatment for major depressive disorder, a debilitating condition that affects approximately 12-17 % of the U.S. population at some point during the individual?s lifetime [1]. Though a full understanding of the mechanisms that underlie antidepressant efficacy in responsive individuals is not yet fully appreciated, emerging evidence supports a role for enhanced excitatory transmission as a mediator of symptomatic remission. Increased excitatory transmission can occur through at least two non-mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms and, in the setting of antidepressant treatment, this likely involves enhanced dendritic arborization and spine formation. A second non- mutually exclusive potential mechanism is that reduced inhibition of excitatory neurons could contribute to antidepressant efficacy. Consistent with this possibility, GABAergic interneuron-mediated cortical inhibition has been linked to reduced ? activity [2], a rhythm that is also diminished in models of depression [3]. Remission of depressive symptoms induced by chronic restraint stress correlates with restoration of ? activity [3]. Due to strong excitatory input, reliable GABA release and fast firing, PV neurons are thought to represent critical pacemakers for synchronous network events [7, 8]. PV neurons also represent the predominant GABAergic neuronal population enveloped by the perineuronal net (PNN), a structure that is thought to localize glutamatergic input [10]. Disruption of the PNN reduces PV excitability [11], and has been linked to enhanced lateral diffusion of glutamate receptor subunits [10]. PNN disruption can also enhance cortical ? activity [13]. The presence of a robust PNN is thus thought to facilitate PV activation, while a relatively weak PNN can instead reduce the same. A limited number of published studies suggest that monoamine modulating antidepressants can reduce integrity of the perineuronal net to potentially facilitate neuroplasticity [14, 15]. Recent work has shown increased PNN deposition with social defeat stress-induced depressive behavior in rats [16]. This is associated with memory impairment that can be rescued with imipramine. Importantly, the mechanisms by which monoamine reuptake inhibitors reduce PNN integrity, and the mechanisms linking increased PNN deposition with depressive behavior, remain largely unexplored. We plan to test the hypothesis that specific monoamine reuptake inhibitors will increase the expression of plasticity-relevant matrix metalloproteinases (MMPs) in brain regions important to depression and that these MMPs will stimulate a) dendritic arborization and spine formation in pyramidal cells as well as b) processing of PNNs that surround PV expressing interneurons. We further propose that select monoamine reuptake inhibitors will act via MMP-dependent mechanisms to a) influence excitatory/inhibitory balance to increase network activity critical to attention and memory (? and sharp wave ripples) and b) ameliorate depression related behaviors.